TNF-α, IL-1, IL-6, IL-8 and COX-II are mainly the proteins (cytokines) produced by immunocompetent cells such as macropharge and neutrophil, which are known as one of the important factors participating in, besides immunomodulatory function and inflammatory symptoms, the hematopoietic system, endocrine system, nervous system and the like.
On the other hand, p38MAPkinase has the action of activating transcription factors such as NF-κB, AP-1 and CREB. These transcription factors bind to the DNA sequence common among TNF-α, IL-1, IL-6, IL-8, COX-II and the like to promote transcription of mRNA which synthesizes the respective cytokines. p38MAPkinase, therefore, has the action to promote the production of cytokines such as TNF-α. While the transcribed mRNA is inactivated upon binding to specific protein and then quickly degraded, p38MAPkinase has an action to dissociate the bonds between mRNA and the specific proteins. In this respect also p38MAPkinase is deemed to contribute to the production of cytokines such as TNF-α.
Accordingly, inhibition of p38MAPkinase leads to inhibition of the production of cytokines such as TNF-α and, therefore, is expected to be useful for the treatment or prophylaxis of the diseases related to the cytokines such as TNF-α, for example, acute inflammation, chronic inflammation, rheumatoid arthritis, osteoarthritis, gout, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastritis, colonic polyposis, large bowel cancer, colon cancer, asthma, bronchitis, bronchial asthma, allergic rhinitis, ARDS (acute respiratory distress syndrome), chronic obstructive pulmonary disease, pulmonary fibrosis, congestive heart disease, ischemic heart disease, myocardial infarction, arteriosclerosis, hypertension, angina, Alzheimer's disease, reperfusion injury, angiitis, cerebrovascular disease, meningitis, multiple sclerosis, osteoporosis, bony sclerosis, Behcet's Syndrome, bone metastasis, multiple myeloma, acute infectious disease, septic shock, sepsis, toxic-shock syndrome, tuberculosis, DIC (disseminated intravascular coagulation), psoriasis, atopic dermatitis, cirrhosis, renal fibrosis, cachexia, AIDS (acquired immunodeficiency syndrome), cancer, autoimmune disease, diabetes, Castleman's disease, mesangial nephritis, endometriosis and preterm delivery.
In the past, as the compounds having p38MAPkinase-inhibiting action, for example imidazole derivatives (cf. Bioorganic & Medicinal Chemistory, Vol. 5, No. 1, 49-64 (1997) and JP Tokuhyo Hei 7 (1995)-503017), pyrazole derivatives (cf. PCT International Publications WO98/52940 Pamphlet and WO0/39116 Pamphlet) and isoxazole derivatives (cf. JP Tokuhyo Hei 11 (1999)-503722, JP2002-179656A, PCT International Publication WO2004/17968 Pamphlet, JP 2000-86657A and PCT International Publication WO2004/22555 Pamphlet) have been proposed. However, these compounds are subject to such problems that most of them exhibit side effects and have not matured as marketable medicines.
Only recently Katerina Leftheris, et al. announced that certain kind of triazine derivatives possessed potent p38MAPkinase-inhibiting action and high speed metabolism, and hence were expected to show reduced side effects and to be prospective antirheumatic medicine (cf. J. Med. Chem., Vol. 47, 6283-6291 (2004)).